Epidermal injury promotes nephritis flare in lupus-prone mice

Abstract

Systemic lupus erythematosus is clinically characterized by episodes of flare and remission. In patients, cutaneous exposure to ultraviolet light has been proposed as a flare trigger. However, induction of flare secondary to cutaneous exposure has been difficult to emulate in many murine lupus models. Here, we describe a system in which epidermal injury is able to trigger the development of a lupus nephritis flare in New Zealand Mixed (NZM) 2328 mice. 20-week old NZM2328 female mice underwent removal of the stratum corneum via duct tape, which resulted in rapid onset of proteinuria and death when compared to sham-stripped littermate control NZM2328 mice. This was coupled with a drop in serum C3 concentrations and dsDNA antibody levels and enhanced immune complex deposition in the glomeruli. Recruitment of CD11b+CD11c+F4/80high macrophages and CD11b+CD11c+F4/80low dendritic cells was noted prior to the onset of proteinuria in injured mice. Transcriptional changes within the kidney suggest a burst of type I IFN-mediated and inflammatory signaling which is followed by upregulation of CXCL13 following epidermal injury. Thus, we propose that tape stripping of lupus-prone NZM2328 mice is a novel model of lupus flare induction that will allow for the study of the role of cutaneous inflammation in lupus development and how crosstalk between dermal and systemic immune systems can lead to lupus flare.

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…Other types of skin injury such as tape stripping and topical application of a TLR7 agonist have been reported to enhance kidney injury in certain lupus models, although disease enhancement was thought to be mediated by macrophages and dendritic cells rather than neutrophils 68,69 . Having demonstrated that tape stripping did not lead to neutrophil recruitment to the kidney, we propose that UV light exposure is different from other types of sterile skin inflammation and is more relevant to SLE.…”

Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon–Induced Up‐Regulation of Interferon Regulatory Factor 1

“…The mechanisms by which the inflammasome impacts SLE pathogenesis are being defined. Upregulation of inflammasome gene expression and inflammasome activity has been identified in both human and murine lupus (1,2,4,6,7,44). Inhibition of caspase 1-or NLRP3-mediated inflammasome signaling in murine models demonstrated that inflammasome pathways contribute to disease pathogenesis via promotion of autoantibody production, endothelial dysfunction, and nephritis (5,9,10,12).…”

Chemokines and Chemokine Receptors in the Development of Lupus Nephritis

“…In lupus-prone mice, CCR1, CCR5, and their ligands are increased in the kidney during LN development [ 24 , 25 , 28 , 49 – 52 , 54 , 75 , 76 ]. Studies have shown that, in nephritic NZB/W F1 mice, both renal T cells and monocytes/macrophages have elevated CCR1 expression on the surface [ 50 ].…”